Methyl Scanning and Revised Binding Mode of 2‑Pralidoxime, an Antidote for Nerve Agent Poisoning

Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood–brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.